title: Adeno-associated virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions.
abstract: Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker-Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of α-dystroglycan (α-DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9-FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of α-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies.
authors.affiliation: McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, North Carolina, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Pei Juan
authors.initials: PJ
authors.lastname: Lu
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Wang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Keramaris
authors.forename: Chunping
authors.initials: C
authors.lastname: Qiao
authors.forename: Bin
authors.initials: B
authors.lastname: Xiao
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Blake
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Qi Long
authors.initials: QL
authors.lastname: Lu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006031:Glycosylation; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000502:physiology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009137:Muscular Dystrophy, Animal / Q000628:therapy*; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014166:Transferases; D019076:Transgenes
chemical_list: D011506:Proteins; D049030:Dystroglycans; D014166:Transferases; C499093:Fkrp protein, mouse; D010430:Pentosyltransferases